Mucormycosis, which is increasing in frequency, most often afflicts patients predisposed by diabetes mellitus with ketoacidosis. A variety of studies have sought to explain the apparent propensity of uncontolled diabetics to develop mucormycotic infections. However, different methodologies have been used, often with conflicting results. The murine models of streptozotocin-induced diabetes provide a rational system for examination of host-immune factors affecting the pathogenesis of mucormycosis and for delineation of specific defects which predispose diabetic subjects to mucormycosis. Host defense to mucormycosis requires either control of spore germination and/or destruction of hyphal forms. Normal but not diabetic alveolar macrophages from mice inhibit spore germination in vitro and in vivo, and appear to be related to the finding that the populations of alveolar macrophages differ between normal and diabetic mice. The populations of alveolar macrophages and monocytes will be characterized by morphologic and immunocytochemical staining. In addition, defects in maturation, activation and function of these cells will be determined. The cells by which the normal host kills fungal spores in the intact host are unknown. Normal and diabetic alveolar macrophages are unable to kill ingested Rhizopus spores in vivo. Using an in vivo killing assay and immunohistochemical staining, the tissue macrophages and leukocyte populations which are involved in spore killing will be determined. The mechanisms of host defense to hyphal forms are also poorly understood. Neutrophils and monocytes cultured with Rhizopus damage hyphae by nonphagocytic mechanisms. Moreover, passive transfer of anti-Rhizopus antibody increases the resistance of immunocom promised mice to mucormycosis, presumably the enhancing leukocyte-mediated damage. The role of specific antisera in host defense will be measured in vitro by hyphal damage assays and in vivo by immunocytochemical studies. Because neutrophils are important in defense, but migration of these cells is impaired in diabetic subjects, the effects of diabetic hyperglycemia and ketoacidosis on chemoattractant inactivation and directly on neutrophil chemotaxis will be investigated. These studies should contribute to our understanding of the pathogenesis of mucormycosis, answer important questions relevant to antimocrobial defense in general, and define specific host defects which may explain the enhanced susceptibility of uncontrolled diabetics to mucormycosis.